Nateglinide is a new class of antidiabetic drug developed jointly by Ajinomoto Co. Inc. and Hoechest Marion Russel of Japan. Its blood sugar lowering effect is rapid following oral administration, since it is short-acting, it prevents hypoglycemia between meals. Nateglinide is indicated to lower blood glucose in patients with type 2 diabetes, where hypoglycemia cannot be adequately controlled by diet, physical exercise and α-glucosaccharase inhibitors.
Nateglinide is chemically termed as (−)-N-(trans-4-isopropylcyclohexyl-1-carbonyl)-D-phenylalanine which is represented by the following formula (I).

Nateglinide was first disclosed in the U.S. Pat. No. 4,816,486 (RE34878).
US20060148902A1 describe hydrolysis of a nateglinide methyl ester in a mixture of water and toluene in the presence of phase transfer catalysts and KOH followed by addition of dilute HCl, filtration, and drying to afford Form B.
U.S. Pat. No. 7,208,622 describes a process in which trans-4-isopropylcyclohexane carbonyl chloride (i.e. a derivative of trans-4-isopropylcyclohexane carboxylic acid) is reacted with D-phenylalanine in the presence of a caustic solution followed by acidification in a mixture of water and acetone and crystallization at 58-72° C. which results in Form H of nateglinide.
Indian application 177/MAS/2003A discloses a process for preparing nateglinide comprising: condensation of D-phenyl alanine methyl ester with trans-4-isopropyl-cyclohexylcarboxylic acid chloride in the presence of a halo solvent such as chloroform and a base (TEA, triethylamine) followed by alkali metal hydrolysis in an alcoholic solvent such as isopropanol. The resulting nateglinide contains the cis isomer and the L-isomer in an amount <0.05%. However, on following the methodology as disclosed in examples 1 and 2, it was observed that, the L-isomer content does not go below 0.22%. This is due to the use of alkali metal hydroxide in the hydrolysis step at ambient temperature. Further, the use of isopropanol in example 2, yields isopropyl ester of nateglinide on acidification with hydrochloric acid. Further, excess D-phenyl alanine methyl ester may either lead to formation of dimeric impurity of formula (D)
during coupling reaction or remains as impurity in the nateglinide ester which needs to be removed by HCl washing prior to hydrolysis.
Indian application 2007/MUM/02380 discloses a process which involves treating an alkyl ester of D-phenylalanine or its acid addition salt with trans-4-isopropylcyclohexanecarboxylic acid halide under biphasic conditions in the presence of a base to give nateglinide alkyl ester, which is hydrolyzed to nateglinide having chiral purity 99.9-100.0%.
US20070043117A1 discloses a process for the preparation of chirally pure nateglinide G, whereby after alkaline hydrolysis of nateglinide alkyl ester, in the mixture of methanol-water; mineral acid is added in two portions such that, in first place mixture of nateglinide base and its alkali salt is isolated whereas in the next step chirally pure nateglinide base is isolated. Thus the process requires two steps to isolate chirally pure nateglinide. Further, the mixture of nateglinide base and it's alkali salt is sticky in nature and hence filtration takes prolong time.
Nateglinide preparation is also disclosed in U.S. Pat. No. 5,463,116, US2004014815A, US2003229249A and WO2008096373.
Most of the prior art methods use a combination of an alkali metal hydroxide and alcoholic solvents during hydrolysis of nateglinide and crystallization of nateglinide. The major drawback of using alcoholic solvents is that some of the nateglinide esterifies back to nateglinide alkyl ester. Further, nateglinide obtained by following the prior art process, is contaminated with cis-isomer, L-isomer, and/or N-(4-isopropyl benzoyl)-D-phenyl alanine (an ethyl analog of nateglinide and dimer impurity), hence repetitive purifications are required to obtain the purified product. This further, thus, reduces yield and purity of the product.
Therefore there is a need to develop a process for the synthesis of nateglinide that overcomes the problems of prior art and that which is simple, cost effective, non-hazardous and industrially viable.